26-OR: METTL3 Is Essential for Exercise-Induced Cardiac Benefits in Diabetic Cardiomyopathy

Abstract

Introduction & Objective: Exercise is an effective strategy in improving functional outcome in patients with diabetic cardiomyopathy (DiaCM). Methyltransferase like 3 (METTL3) is a N⁶-Methyladenosine (m6A) methyltransferase that has been implicated in cardiac development and disease. However, the role of METTL3 in DiaCM and in cardiac benefits of exercise on DiaCM, are unclear. Methods: METTL3 floxed mice were injected with AAV9 encoding cardiac troponin-T (cTnT)-driven Cre recombinase to knockout METTL3 in cardiomyocytes (CMs). CM-specific METTL3 knockout mice, METTL3 floxed mice, and their wild-type littermates were subjected to either chow diet or high-fat (HFD) diet feeding and injection of streptozotocin (STZ) to induce DiaCM, followed by an eight-week exercise training. Some of the HFD+STZ mice were injected with AAV9 encoding cTnT-driven METTL3 to overexpress METTL3 in CMs. Results: Mice treated with HFD+STZ displayed increased E/e’ and reduced global longitudinal strain, fractional shortening (FS) and cardiac METTL3 protein expression (p<0.05 for all). Exercise improved diastolic (E/e’: Sedentary: -34.69 ± 1.25 vs Exercise: -29.48 ± 1.92, p=0.04, n=10), systolic function (FS: Sedentary: 54.24% ± 2.94 vs Exercise: 62.33% ± 2.12, p=0.04, n=10) and cardiac METTL3 protein expression. These effects of exercise were canceled by CM-specific METTL3 knockout (FS: Control: 57.17% ± 1.85 vs Knockout: 28.49% ± 3.98, p<0.001, n=8). In HFD+STZ mice, CM-specific METTL3 overexpression improves diastolic and systolic (FS: Control: 44.31% ± 2.2 vs Overexpression: 50.56% ± 1.64, p=0.03, n=8) functions. METTL3 functioned by increasing m6A deposition in YBX-1 and promoted its transcription. CM-specific YBX-1 overexpression improved diastolic and systolic functions as well as reduced cardiac oxidative stress. Conclusion: METTL3 regulates DiaCM through YBX-1 and is essential for cardiac benefits of exercise in DiaCM. METTL3 is a promising therapeutic target for combating DiaCM. Disclosure C. Wang: None. J. Kang: None. A. Sugai-Munson: None. Z. Liu: None. W. Yao: None. H. Li: None. Funding National Institutes of Health (R21AG077040); American Heart Association (20CDA35310184)